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Feasibility study of an alternating schedule of radiotherapy and chemotherapy in advanced uterine cervical carcinoma
Radiotherapy and Oncology, 12 (1988) 121-127 Elsevier RTO 00450
y of an alternatin erapy in a C. Haiel, M. George2, M.H. Pejovic3, D. Chassagne 0. Ee IFloch and J.
oriot4, J. Fentons,
‘Department ofRadiotherapy and Uniti INSERM 241, Institut Gustave-Roussy. Viikju$ France, Departments qf JG~~lpc&~~ arl$ =Medical Statistics, lnstitut Gustave-Roussy, Villeju$ France, 4Department of Radiotherapy. Centre G.F. Leclerc, D!ion, France, sDepartment qf Radiotherapy, Institut Curie, Paris, France, bDepartnlent of Radiotherapy, CHU Bretonneau, Tours, France, and 7 Department of Medicine, Centre F. Bacfesse, Caen, France
(Received 25 April 1985, revision received 28 December 1987, accepted 14 January 1988)
Key words: Cervical carcinoma; Radiochemotherapy alternating schedule
From July 1981 to April 1982,36 patients with advanced cervical carcinoma stage III (24 patients)
and stage
IV (12 patients) entered a feasibility study of a radiotherapy and chemotherapy combination. The first three chemotherapy courses consisted of &platinum alone (50 mg/m2) and were interdigitated with radiotherapy. Six more courses composed of an association of c&platinum (50 mg/m2) and cyclophosphamide (400 mg/m2) were given after the completion of radiotherapy. Radiotherapy was delivered in two courses of 25 Gy separated by a gap of 2 weeks. The overall 4-year survival rate was 35% (95% CI: 22%). The 4-year survival rate, cumulative loco-regional failure rate, and cumulative metastasis rate were respectively 44% (95% CI: 20%), 56% (95% CI: 21%), and 30% (95% CI: 21%) in stage III and 28% (95% CI: 27%), 83% (95% CI: 21%) and 74% (95% CI: 30%) in stage IV. The incidence of immediate and late complications was low: no patient had her radiotherapy stopped because of an intolerance and two patients had their chemotherapy stopped because of an haematological intolerance. Only one patient presented a severe late clinical complication (small bowel injury).
Introdwtion
The 5-year survival rate of patients with advanced cervical carciuoma treated with radiotherapy alone Address for correspondence: Christine Haie, Service de CuriethCrapie, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif, France.
ranges from 30 to 42% in stage III and from 7 to 15% in stage IV [1,9,13,14,17]. The loco-regional control of advanced cervical carcinoma remains the major problem: the pelvic failure rate can reach 40-50% in stage IIIb cervical carcinoma [9,13,17]. The poor survival rate is also partly due to a high metastasis incidence which can reach 25% in stage III [9]. Several approaches have been proposed to
0167-8140/88/$03.50 $J 1988 Elsevier Science Publishers B.V. (Biomedical Division)
122 improve the local control as well as the management of microscopic distant metastasis. Prophylactic para-aortic irradiation has been performed under the leadership of the EORTC radiotherapy group in a randomized trial in patients with advanced cervical carcinoma. NO improvement in the survival was observed [9]. A randomized trial with or without misonidazole in stage IIIb cervical carcinoma showed no benefit in local control nor survival [5,16]. The role of chemotherapy in the management of advanced cervical carcinoma has not been yet defined, As this tumour appeared to be resistant to cytotoxic drugs, chemotherapy was first used as a salvage treatment, after the failure of primary treatment [8]. In such situations, the most effective drug is cis-dichlorodiammine-platinum (cDDP) and its optimal dose has been estimated by Thigpen et al. [24] to be 50 mg/m2, since there is no dose-response enhancement with this drug. Other drugs have been reported to be effective against carcinoma of the cervix [ 181. Among them, cyclophosphamide (CPM) seems to be effective and a synergism between cDDP and CPM has even been reported [29]. Chemotherapy in association with radiotherapy has been reported as an interesting concept, as this association may increase the local control rate by mechanisms of either potentiation or additivity on tumour cells [19,23,26]. The second advantage of such an association could be the spatial cooperation [23] which could improve local control and reduce the risk of metastasis. This strategy requires radiotherapy and chemotherapy to be given at full doses to be effective. The main risk of such a combination is an enhanced toxicity. In order to reduce the toxicity risk, this chemotherapy-radiotherapy combination has been reported to be better tolerated if a time interval of one week was observed between radiotherapy and chemotherapy [26]. This time interval of one week seemed to be long enough to allow the repopulation of normal tissue. In 1981, we initiated a feasibility study of an alternating schedule of radiotherapy and chemotherapy in patients with advanced cervical carcinoma. The results of this treatment are reported and discussed.
Materials en methods
From July 1981 to April 1982, five French centres have treated 36 patients with cervical carcinoma stage III and IV (UICC classification) with an alternating schedule of radiotherapy and chemotherapy. Patients younger than 70 years without prior pelvic or abdominal radiotherapy, without acute or sub-acute site of infection or other serious disease such as diabetes, and mental disorders, entered the study. Patients had to have normal renal and haematological functions (creatininaemia < 110 mmol/ml), leukocytes > 4000/mm3 and platelets > 130000/mm3 to be eligible). The staging of the disease was performed by three physicians, under anaesthesia whenever possible. The assessment of tumour extent included cystoscopy, proctoscopy, complete blood counts and blood chemistry, chest X-ray, intravenous pyelogram (IVP) and lymphangiography. Sample size. Previous data showed that the proportion of late digestive complications was 10% with the standard treatment [6,9,10,13]. If the observed complication rate with the treatment combining radiotherapy and chemotherapy reached 25%, 35 patients were required to judge this trea:ment unacceptable with 80% power and 25% type 1 error [22]. Patient population.
The mean age of the 36 patients was 53 years (SD.: 10 years). The median Karnofsky index was 80 (range 50 to 100). There were 35 epidermoid carcinoma and one adenocarcinema. Twenty-four patients presented with stage III and 12 with stage IV. Among patients with stage III, seven had an ureteral obstruction on the IVP. Among patients with stage IV, one had stage IVa with a bladder involvement .and 11 had stage IVb: 6 with para-aortic node involvement, 2 para-aortic and bladder involvement, one para-aortic, and supra-clavicular modes and 2 pulmonary metastases. Treatment Chemotherapy
The first course of chemotherapy
consisted of
123 WBBKS 1
TREATMENT MSIGNMBNT
(1) Fourteen patients received the nine planned
CDDP
courses. (2) Twelve other patients received 6-8 courses. Chemotherapy was interrupted for the following reasons: progressive disease (S), intercurrent disease (I), leukopenia grade 3 (2) and protocol violation (4). (3) Ten other patients received less than six courses. Causes of chemotherapy interruption were: progressive disease (4), intercurrent disease (3), refusal (1) and protocol violation (2).
50 mg/eqm
2 RT
25 Gy
6 6
CDDP
50
mg/aqm
I
RT
25 Gy
Finally, of the total of 36 patients, 30 received the three courses interdigitated with radiotherapy.
10 11
CDDP 50 mg/sqa
12
1
ROOST
10 Gy
14
15
CDDP 60 ?g/sqm ? + CPM 600 mg/aqm
19
CDDP 50 mg/aqm + CPM 600 rag/i-an AND CONTINUASION BVBRY 4 FOR A TOTAL OF 6 COURSBS
Fig. I. Schedule of the radiotherapy-chemotherapy tion.
WEEKS
combina-
cDDP alone and was delivered one week before the beginning of radiotherapy. A second course was delivered, 5 weeks later, in the middle of a IS-day gap separating the two radiation courses (Fig. 1). A third course was delivered the tenth week, i.e. one week after the end of radiotherapy. The dosage of cDDP was 50 rng/m* and was given with the usual pre- and post-hydratation. One week after the completion of the whole radiotherapy, a chemotherapy combining cDDP 50 mg/m* and CPM 600 mg/m* was delivered every 28 days. Six cycles of the chemotherapy were administered so that a total of nine courses was achieved. The overall treatment schedule is reported in Fig. 1. Of the 36 patients, three groups can be made:
External radiotherapy delivered 50 Gy to the pelvis administered in two courses of 25 Gy separated by a gap of 2 weeks (Fig. 1). Five fractions of 1.7-1.8 Gy were delivered weekly using megavoltage machines with a photon energy higher than 18 MV. The “box” technique was performed using four fields: anterior, posterior and two lateral fields. The pairs of opposed fields were treated daily. Para-aortic node irradiation was performed up to 45 Gy when involvement of this area was diagnosed on lymphangiogram, according to the criteria of nodal involvement published by Piver and Wallace [20]. Two weeks after the completion of external radiotherapy, a brachytherapy boost was delivered. Ten Gy were delivered, according to the recommendations of the ICRU report no. 38 [1 11.For patients in whom brachytherapy could not be achieved, a IO-Gy boost was delivered by external radiotherapy in a reduced pelvic volume. Of the 36 patients, 28 patients received pelvic irradiation and eight pelvic and para-aortic irradiation. External radiotherapy was delivered in two courses, as previously defined, in 32 patients. Four patients had their radiotherapy performed in one course (median dose: 43 Gy) for the following reasons: protocol violation (1) and intercurrent disease (3) leading to a chemotherapy contraindication. Brachytherapy was performed in 30 patients: 28 with cesium-137, one with iridium-192 and one with
124
an association of cesium-137 and iridium- 192. Ten Gy were delivered to an average volume of 292 cm3 (138-409). The average dimensions of the pearshaped treated volume were height: 105 mm (85 120), width: 78 mm (55-109) and thickness: 75 mm (48-l 10). The six remaining patients had a boost delivered by external radiotherapy. Results Events
The 4-year overall survival rate estimated using the Kaplan-Meier method [15] was 35% (95% CI: 22%). In stage III, the 4-year survival rate was 44% (95% CI: 20%) and 28% (95% CI: 27%) in stage IV (Fig. 2). The 4-year overall cumulative locu-regional failure rate (including tumour evolution and recurrences) with or without distant metastasis was 67% (95% CI: 20%); this rate was 56% (95% CI: 21%) in stage III and 83% (95% CI: 21%) in stage IV. Among the 30 patients who had received at least three chemotherapy courses, this 4-year cumulative loco-regional failure rate was 59% (95% CT: 20%). The 4-year overall cumulative metastasis rate was 50% (95% CI: 21%) in stage III and 74% (95% Cl: 30%) in stage IV. Among the 30 patients who had received at least three chemotherapy courses the 4-year cumulative metastasis rate was 45% (95% CT: 21%). Complications
TABLE I Number of patients with clinical intolerance
Vulvovaginitis Proctitis Diarrhoea Nausea/Vomiting Cystalgia
during treatment.
1st Radiotherapy course
course
2 2 0 1 0
5 4 8 8” 1
a One patient with grade 3. All patients except one have complications to the WHO classification [28].
2nd Radiotherapy
grade l-2 according
classification [28]. No lethal complication was observed. Clinical intolerances during treament are summarized in Table I. No treatment interruption was due to clinical intolerance. Biological toxicity during treatment is reported in Table II. Two patients with leukocyte toxicity grade 3 had their chemotherapy interrupted. Complications were considered as “late” when they occurred at least 2 months after the end of the least chemotherapy course. Late clinical complications were graded according to a glossary previously published [3]. Seven patients presented at least one late clinical complication. Details of complications are summarized in Table III. Ten patients presented at least one “late” biological complication, 2 months at least after the end of the last chemotherapy course. Details of late biological complications are given in Table IV.
Acute toxicity was graded according to the WHO Discussion
; 8.4 6.5 e.e I
A.
e
I
I
6
12
I
12
I
24
I
36
I
36
I
42
48
IaNTHs ____
STROE III 6lmE IV
me41 ON=121
Fig. 2. Survival by stage (Kaplan-Meier
method).
74
In this series combining radiotherapy and chemotherapy, the treatment tolerance was good. Radiotherapy was delivered in two courses, as previously planned, in 94% of the patients. All of them received at least 42 Gy. Radiotherapy was still feasible, even with the addition of chemotherapy. Chemotherapy tolerance in this type of combination was good. Haematological depression during treatment was mild and led to a chemotherapy interruption in only two cases. Chemotherapy interruptions,
125 TABLE II Number of patients with biological toxicity during treatment
After After After After After
the the the the the
1st chemotherapy course 1st radiotherapy course 2nd radiotherapy course 4th chemotherapy course 9th chemotherapy course
according to the time schedule and to the type of toxicity”.
HB
WBC
Platelets
Renal
Hepatic
1 4 (1) 8 (i) 8 (2) 8 (2)
1 4 2 13 (2) 2
0 0 0 0 0
0 2 0 4 4 (2)
0 0 0
a Biological toxicity was graded according to the WHO classification [28]. The number in parentheses patients with grade 3 toxicity.
prior to the nine planned courses, were related to progressive disease in nine patients. In these nine patients, chemotherapy was unable to decrease tumour masses or to prevent metastases. This lack of efficacy could be due to the use of cDDP alone. We choose the use of cDDP alone purposely because of its low myelo- and dermatotoxicity. At the time when we initiated this feasibility study, we had no idea of the toxicity of this type of combined radiotherapy and chemotherapy treatment. As a matter of fact, more aggressive chemotherapy has later led to much higher incidences of digestive and skin toxicities [27]. The severe late complication rate from this combined treatment is not different from the rate quoted with the same glossary in patients treated with TABLE III Four-year
clinical complication?.
Type of complication
Proctitis Diarrhoea Small bowel injury Cystitis Bladder incontinence Renal Pelvis fibrosis
No. of patients
3 2 1 1 1 5 4
corresponds
TABLE IV
rate (%)b
(SD.)
Four-year biological complications. ing to grade and type”.
20.5 6.5 4.8 11.1 8.3 21.4 18.8
(9.9) (4.5) (4.7) (10.5)
a Complications were graded according to a glossary published in 1980 [3]. b Estimated using Kaplan-Meier method.
to the number of
the same radiotherapy doses without chemotherapy [8]. NO lethal complication was observed. This type of association did not increase the 4-year complication rate. It is not possible from this non-randomized trial to determine whether the combination of chemotherapy and radiotherapy is superior to the use of radiotherapy alone. The 4-year survival rate is not different from the rate observed with radiation therapy only [8]. The 4-year loco-regional failure rate remains high. However, all the patients had either advanced stage III or stage IV disease. In this association, if chemotherapy and radiotherapy had an additive mechanism, small tumours would be expected to have a better response-rate than larger tumours [2,22]. Moreover, in this type of association, radiotherapy is lenghtened with a gap of 2 weeks in the middle of the treatment. Since the time we initiated this trial, some authors have suggested that, when overall treatment time is lengthenod,
4-Year complication
(8) (8.6) (8.7)
2 (1) 2
Grade
Type
Haemoglobin White blood counts Creatininaemia a Complications tion [28].
Number of patients accord-
1
2
3
2 3 2
2 2 2
2
were graded according to the
WHOclassifica-
126 radioresistance might be increased [7,25]. Repopulation could play an important role in this increased radioresistance. In conclusion, chemotherapy interdigitated with radiotherapy in the treatment of advanced cervical carcinoma is feasible without toxicity enhancement. It is impossible to determine the efficacy of such a combined treatment because of the small number of patients. However, we have stopped this type of treatment, mainly because of the poor cost-benefit ratio of such an alternating schedule. The concomitant use of chemotherapy and radiation therapy couid be an alternative. Chemotherapeutic agents like cDDP or hydroxyurea given during radiotherapy have been reported to improve the survival [4,21]. Prospective studies comparing radiotherapy with radiotherapy and chemotherapy are needed in advanced cervical carcinoma. Another alternative is the use of “new” radiosensitizers. RO-8799 is presently under evaluation in a prospective randomized trial in uterine cervix carcinoma, in which two of us are involved.
References Ballow, S., Bennan, M., Lagasse, L., Petrilli, E. and Castaldo, F. Survival after extraperitoneal pelvic and para-aortic lymphadenectomy and radiation therapy in cervical carcinoma. Obstet. Gynecol. 57: 90-95, 1981. Blake, P.R., Branson, A.N. and Lambert, H.E. Combined radiotherapy and chemotherapy for advanced carcinoma of the cervix. Clin. Radiol. 37: 4651169, 1986. Chassagne, D. Cancer du co1 uterin. Glossaire ou lexique des complications. Bull. Cancer (Paris) 67: 120-125, 1980. Choo, Y.C., Choy, T.K., Wong, L.C. and Ma, H.K. Potentiation of radiotherapy by cis-dichlorodiammine platinum(H) in advanced cervical carcinoma. Gynecol. Oncol. 23: 94-100, 1986. Dische, S. Radiotherapy of cervical cancer. Clin. Obstet. Gynecol. 12: 203-227, 1985. Einhorn, N. Frequency of severe complications after radiation therapy for cervical carcinoma. Acta Radiol. Ther. Phys. Biol. 14: 42-48, 1975. Fowler, 3.F. The significance of proliferation rate in normal tissues and tumors. proceedings of the 16th International Congress of Radiology, HawaI, July, 201-206, 1985. Gerbaulet, A., Rochard, F. and George, M. Traitement des recidives et des metastases du cancer du col uttrin. Rev. Prat. 31: 1979-1985, 1981.
9 Haie, C., Pejovic, M.H., Gerbaulet, A., Horiot, J.C., Pourquier, H., Delouche, J., Brune, D., Fenton, J., Pizzi, G., Bey, P., Brossel, R., Pillement, P., Volterrani, F. and Chassagne, D. Is prophylactic para-aortic irradiation worthwile in the treament of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group. Radiother. Oncol. 11:101-l 12, 1988. 10 Hamberger, A.D., Abdurrahman, U., Gershenson, D.M. and Fletcher, G.H. Analysis of the severe complications of irradiation of carcinoma of the cervix: whole pelvis irradiation and intracavitary radium. Int. J. Radiat. Oncol. Biol. Phys. 9: 367-371, 1983. Hiilesmaa, V.K., Vesterinen, E., Nienminen, U. and Grohn, 11 P. Carcinoma of the uterine cervix stage III: a report of 311 cases. Gynecol. Oncol. 12: 99-106, 1981. 12 International Commission on Radiation Units and Measurements. Dose and volume specification for reporting intracavitary therapy in gynecology. ICRU Report 38, Washington, D.C., 1984. 13 Jampolis, S., Andras, E. and Fletcher, G.H. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the uterine cervix. Radiology 115: 68 l-685, 1975. 14 Jobson, V., Sirtanner, R. and Averette, H. Therapy and survival of early invasive carcinoma of the cervix uteri with metastases to the pelvic nodes. Surg. Gynecol. Obstet. 151: 27-29, 1980. 15 Kaplan, E.L. and Meier, P. Non-parametric estimation from incomplete observations. J. Am. Statist. Assoc. 53: 457-481, 1958. 16 The Medical Research Council. Trial of Misonidazole in carcinoma of the cervix. A report from the MRC Working Party on Misonidazole for cancer of the cervix. Br. J. Radiol. 57: 491-499, 1984. 17 Montana, G.S., Fowler, WC., Waria, M.A., Walton, L.A. and Mack, Y. Analysis of results of radiation therapy for stage III carcinoma of the cervix. Proceedings of the American Society for Therapeutic Radiology and Oncology (Abstr., 119). Int, J. Radiat. Oncol. Biol. Phys. 38: 10, 1984. 18 Muscato, MS., Perry, M.C. and Yarbro, J.W. Chemotherapy of cervical cancer. Semin. Oncol. 9: 373-387, 1982. 19 Peckham, M.J. and Collis, C.H. Clinical objectives and normal tissue responses in combined chemotherapy and radiotherapy. Bull. Cancer (Paris) 68: 132-141, 1981. 20 Piver, M.S., Wallace, S. and Castro, J.R. The accuracy of lymphangiography in carcinoma of the uterine cancer. Am. J. Roentgenol. Radiat. Ther. Nucl. Med. 111: 278-283,197l. 21 Piver, MS., Krishnamsetty, R.M. and Emrich, L.J. Survival of non-surgically staged patients with negative lymphangiograms who had stage IIB carcinoma of the cervix treated by pelvic irradiation plus hydroxyurea. Am. J. Obstet. Gynecol. 151: 1006-1008, 1985. 22 Shoenfeld, D. Statistical considerations for pilot studies. Int. J. Radiat. Oncol. Biol. Phys. 6: 371-374, 1980. 23 Steel, G.G., Peckam, D. SC. and M. Exploitable mechan-
isms in combined radiotherapy-chemotherapy: the concept of additivity. Int. J. Radia:. Gncol. Biol. Phys. 5: 8.5-91. 1979. 24 Thigpen, T.. Shingleton, H.. Homesley, H.. Lagasse, L. and Blessing, J. Cisplatinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: a phase II study of Gynecologic Oncology Group. Cancer 48: 899-903, 1981. 25 Trott, K.R. Proliferation kinetics of tumor cells during treatment as a basis for radiaton resistance. Proceedings of the 16th International Congress of Radiology, Hawai’, July, 159-163, 1985. 26 Tubiana, M. Chronologie d’administration des drogues cytotoxiques et associations chimiotherapie-radiothtrapie. Bull. Cancer (Paris) 71: 301-312, 1984.
27 Van den Burg, M.E.L., Subandono. A.J., Mangioni. C.. De Oliveira. CF., Zola, P., Pecorelli, S., Van Oosterom, A.T. and Vermorken, J.B. Vincristine. Bleomycin, MitomycinC, Cisplatin as additive treatment to radiotherapy in poor risk patients with squamous cell carcinoma of the uterine cervix. Proceedings ESMO IO (Abstra) 264, 1984. 28 WHO. Handbook for reporting results of cancer treatment. World Health Organization, Geneva, 1979. 29 Woodman, R.J., Sirica, A.E. and Gang, N. The enhanced therapeutic effect of cisplatinum (II) Diamminodirhloride against K 1210 leukemia when combined with Cyclophosphamide or 1, 2-bis (3.5 Dioxopiperazine-I-yl) propane or several other antitumor agents. Chemotherapy 18: 169-l 83, 1973.
y of an alternatin erapy in a C. Haiel, M. George2, M.H. Pejovic3, D. Chassagne 0. Ee IFloch and J.
oriot4, J. Fentons,
‘Department ofRadiotherapy and Uniti INSERM 241, Institut Gustave-Roussy. Viikju$ France, Departments qf JG~~lpc&~~ arl$ =Medical Statistics, lnstitut Gustave-Roussy, Villeju$ France, 4Department of Radiotherapy. Centre G.F. Leclerc, D!ion, France, sDepartment qf Radiotherapy, Institut Curie, Paris, France, bDepartnlent of Radiotherapy, CHU Bretonneau, Tours, France, and 7 Department of Medicine, Centre F. Bacfesse, Caen, France
(Received 25 April 1985, revision received 28 December 1987, accepted 14 January 1988)
Key words: Cervical carcinoma; Radiochemotherapy alternating schedule
From July 1981 to April 1982,36 patients with advanced cervical carcinoma stage III (24 patients)
and stage
IV (12 patients) entered a feasibility study of a radiotherapy and chemotherapy combination. The first three chemotherapy courses consisted of &platinum alone (50 mg/m2) and were interdigitated with radiotherapy. Six more courses composed of an association of c&platinum (50 mg/m2) and cyclophosphamide (400 mg/m2) were given after the completion of radiotherapy. Radiotherapy was delivered in two courses of 25 Gy separated by a gap of 2 weeks. The overall 4-year survival rate was 35% (95% CI: 22%). The 4-year survival rate, cumulative loco-regional failure rate, and cumulative metastasis rate were respectively 44% (95% CI: 20%), 56% (95% CI: 21%), and 30% (95% CI: 21%) in stage III and 28% (95% CI: 27%), 83% (95% CI: 21%) and 74% (95% CI: 30%) in stage IV. The incidence of immediate and late complications was low: no patient had her radiotherapy stopped because of an intolerance and two patients had their chemotherapy stopped because of an haematological intolerance. Only one patient presented a severe late clinical complication (small bowel injury).
Introdwtion
The 5-year survival rate of patients with advanced cervical carciuoma treated with radiotherapy alone Address for correspondence: Christine Haie, Service de CuriethCrapie, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif, France.
ranges from 30 to 42% in stage III and from 7 to 15% in stage IV [1,9,13,14,17]. The loco-regional control of advanced cervical carcinoma remains the major problem: the pelvic failure rate can reach 40-50% in stage IIIb cervical carcinoma [9,13,17]. The poor survival rate is also partly due to a high metastasis incidence which can reach 25% in stage III [9]. Several approaches have been proposed to
0167-8140/88/$03.50 $J 1988 Elsevier Science Publishers B.V. (Biomedical Division)
122 improve the local control as well as the management of microscopic distant metastasis. Prophylactic para-aortic irradiation has been performed under the leadership of the EORTC radiotherapy group in a randomized trial in patients with advanced cervical carcinoma. NO improvement in the survival was observed [9]. A randomized trial with or without misonidazole in stage IIIb cervical carcinoma showed no benefit in local control nor survival [5,16]. The role of chemotherapy in the management of advanced cervical carcinoma has not been yet defined, As this tumour appeared to be resistant to cytotoxic drugs, chemotherapy was first used as a salvage treatment, after the failure of primary treatment [8]. In such situations, the most effective drug is cis-dichlorodiammine-platinum (cDDP) and its optimal dose has been estimated by Thigpen et al. [24] to be 50 mg/m2, since there is no dose-response enhancement with this drug. Other drugs have been reported to be effective against carcinoma of the cervix [ 181. Among them, cyclophosphamide (CPM) seems to be effective and a synergism between cDDP and CPM has even been reported [29]. Chemotherapy in association with radiotherapy has been reported as an interesting concept, as this association may increase the local control rate by mechanisms of either potentiation or additivity on tumour cells [19,23,26]. The second advantage of such an association could be the spatial cooperation [23] which could improve local control and reduce the risk of metastasis. This strategy requires radiotherapy and chemotherapy to be given at full doses to be effective. The main risk of such a combination is an enhanced toxicity. In order to reduce the toxicity risk, this chemotherapy-radiotherapy combination has been reported to be better tolerated if a time interval of one week was observed between radiotherapy and chemotherapy [26]. This time interval of one week seemed to be long enough to allow the repopulation of normal tissue. In 1981, we initiated a feasibility study of an alternating schedule of radiotherapy and chemotherapy in patients with advanced cervical carcinoma. The results of this treatment are reported and discussed.
Materials en methods
From July 1981 to April 1982, five French centres have treated 36 patients with cervical carcinoma stage III and IV (UICC classification) with an alternating schedule of radiotherapy and chemotherapy. Patients younger than 70 years without prior pelvic or abdominal radiotherapy, without acute or sub-acute site of infection or other serious disease such as diabetes, and mental disorders, entered the study. Patients had to have normal renal and haematological functions (creatininaemia < 110 mmol/ml), leukocytes > 4000/mm3 and platelets > 130000/mm3 to be eligible). The staging of the disease was performed by three physicians, under anaesthesia whenever possible. The assessment of tumour extent included cystoscopy, proctoscopy, complete blood counts and blood chemistry, chest X-ray, intravenous pyelogram (IVP) and lymphangiography. Sample size. Previous data showed that the proportion of late digestive complications was 10% with the standard treatment [6,9,10,13]. If the observed complication rate with the treatment combining radiotherapy and chemotherapy reached 25%, 35 patients were required to judge this trea:ment unacceptable with 80% power and 25% type 1 error [22]. Patient population.
The mean age of the 36 patients was 53 years (SD.: 10 years). The median Karnofsky index was 80 (range 50 to 100). There were 35 epidermoid carcinoma and one adenocarcinema. Twenty-four patients presented with stage III and 12 with stage IV. Among patients with stage III, seven had an ureteral obstruction on the IVP. Among patients with stage IV, one had stage IVa with a bladder involvement .and 11 had stage IVb: 6 with para-aortic node involvement, 2 para-aortic and bladder involvement, one para-aortic, and supra-clavicular modes and 2 pulmonary metastases. Treatment Chemotherapy
The first course of chemotherapy
consisted of
123 WBBKS 1
TREATMENT MSIGNMBNT
(1) Fourteen patients received the nine planned
CDDP
courses. (2) Twelve other patients received 6-8 courses. Chemotherapy was interrupted for the following reasons: progressive disease (S), intercurrent disease (I), leukopenia grade 3 (2) and protocol violation (4). (3) Ten other patients received less than six courses. Causes of chemotherapy interruption were: progressive disease (4), intercurrent disease (3), refusal (1) and protocol violation (2).
50 mg/eqm
2 RT
25 Gy
6 6
CDDP
50
mg/aqm
I
RT
25 Gy
Finally, of the total of 36 patients, 30 received the three courses interdigitated with radiotherapy.
10 11
CDDP 50 mg/sqa
12
1
ROOST
10 Gy
14
15
CDDP 60 ?g/sqm ? + CPM 600 mg/aqm
19
CDDP 50 mg/aqm + CPM 600 rag/i-an AND CONTINUASION BVBRY 4 FOR A TOTAL OF 6 COURSBS
Fig. I. Schedule of the radiotherapy-chemotherapy tion.
WEEKS
combina-
cDDP alone and was delivered one week before the beginning of radiotherapy. A second course was delivered, 5 weeks later, in the middle of a IS-day gap separating the two radiation courses (Fig. 1). A third course was delivered the tenth week, i.e. one week after the end of radiotherapy. The dosage of cDDP was 50 rng/m* and was given with the usual pre- and post-hydratation. One week after the completion of the whole radiotherapy, a chemotherapy combining cDDP 50 mg/m* and CPM 600 mg/m* was delivered every 28 days. Six cycles of the chemotherapy were administered so that a total of nine courses was achieved. The overall treatment schedule is reported in Fig. 1. Of the 36 patients, three groups can be made:
External radiotherapy delivered 50 Gy to the pelvis administered in two courses of 25 Gy separated by a gap of 2 weeks (Fig. 1). Five fractions of 1.7-1.8 Gy were delivered weekly using megavoltage machines with a photon energy higher than 18 MV. The “box” technique was performed using four fields: anterior, posterior and two lateral fields. The pairs of opposed fields were treated daily. Para-aortic node irradiation was performed up to 45 Gy when involvement of this area was diagnosed on lymphangiogram, according to the criteria of nodal involvement published by Piver and Wallace [20]. Two weeks after the completion of external radiotherapy, a brachytherapy boost was delivered. Ten Gy were delivered, according to the recommendations of the ICRU report no. 38 [1 11.For patients in whom brachytherapy could not be achieved, a IO-Gy boost was delivered by external radiotherapy in a reduced pelvic volume. Of the 36 patients, 28 patients received pelvic irradiation and eight pelvic and para-aortic irradiation. External radiotherapy was delivered in two courses, as previously defined, in 32 patients. Four patients had their radiotherapy performed in one course (median dose: 43 Gy) for the following reasons: protocol violation (1) and intercurrent disease (3) leading to a chemotherapy contraindication. Brachytherapy was performed in 30 patients: 28 with cesium-137, one with iridium-192 and one with
124
an association of cesium-137 and iridium- 192. Ten Gy were delivered to an average volume of 292 cm3 (138-409). The average dimensions of the pearshaped treated volume were height: 105 mm (85 120), width: 78 mm (55-109) and thickness: 75 mm (48-l 10). The six remaining patients had a boost delivered by external radiotherapy. Results Events
The 4-year overall survival rate estimated using the Kaplan-Meier method [15] was 35% (95% CI: 22%). In stage III, the 4-year survival rate was 44% (95% CI: 20%) and 28% (95% CI: 27%) in stage IV (Fig. 2). The 4-year overall cumulative locu-regional failure rate (including tumour evolution and recurrences) with or without distant metastasis was 67% (95% CI: 20%); this rate was 56% (95% CI: 21%) in stage III and 83% (95% CI: 21%) in stage IV. Among the 30 patients who had received at least three chemotherapy courses, this 4-year cumulative loco-regional failure rate was 59% (95% CT: 20%). The 4-year overall cumulative metastasis rate was 50% (95% CI: 21%) in stage III and 74% (95% Cl: 30%) in stage IV. Among the 30 patients who had received at least three chemotherapy courses the 4-year cumulative metastasis rate was 45% (95% CT: 21%). Complications
TABLE I Number of patients with clinical intolerance
Vulvovaginitis Proctitis Diarrhoea Nausea/Vomiting Cystalgia
during treatment.
1st Radiotherapy course
course
2 2 0 1 0
5 4 8 8” 1
a One patient with grade 3. All patients except one have complications to the WHO classification [28].
2nd Radiotherapy
grade l-2 according
classification [28]. No lethal complication was observed. Clinical intolerances during treament are summarized in Table I. No treatment interruption was due to clinical intolerance. Biological toxicity during treatment is reported in Table II. Two patients with leukocyte toxicity grade 3 had their chemotherapy interrupted. Complications were considered as “late” when they occurred at least 2 months after the end of the least chemotherapy course. Late clinical complications were graded according to a glossary previously published [3]. Seven patients presented at least one late clinical complication. Details of complications are summarized in Table III. Ten patients presented at least one “late” biological complication, 2 months at least after the end of the last chemotherapy course. Details of late biological complications are given in Table IV.
Acute toxicity was graded according to the WHO Discussion
; 8.4 6.5 e.e I
A.
e
I
I
6
12
I
12
I
24
I
36
I
36
I
42
48
IaNTHs ____
STROE III 6lmE IV
me41 ON=121
Fig. 2. Survival by stage (Kaplan-Meier
method).
74
In this series combining radiotherapy and chemotherapy, the treatment tolerance was good. Radiotherapy was delivered in two courses, as previously planned, in 94% of the patients. All of them received at least 42 Gy. Radiotherapy was still feasible, even with the addition of chemotherapy. Chemotherapy tolerance in this type of combination was good. Haematological depression during treatment was mild and led to a chemotherapy interruption in only two cases. Chemotherapy interruptions,
125 TABLE II Number of patients with biological toxicity during treatment
After After After After After
the the the the the
1st chemotherapy course 1st radiotherapy course 2nd radiotherapy course 4th chemotherapy course 9th chemotherapy course
according to the time schedule and to the type of toxicity”.
HB
WBC
Platelets
Renal
Hepatic
1 4 (1) 8 (i) 8 (2) 8 (2)
1 4 2 13 (2) 2
0 0 0 0 0
0 2 0 4 4 (2)
0 0 0
a Biological toxicity was graded according to the WHO classification [28]. The number in parentheses patients with grade 3 toxicity.
prior to the nine planned courses, were related to progressive disease in nine patients. In these nine patients, chemotherapy was unable to decrease tumour masses or to prevent metastases. This lack of efficacy could be due to the use of cDDP alone. We choose the use of cDDP alone purposely because of its low myelo- and dermatotoxicity. At the time when we initiated this feasibility study, we had no idea of the toxicity of this type of combined radiotherapy and chemotherapy treatment. As a matter of fact, more aggressive chemotherapy has later led to much higher incidences of digestive and skin toxicities [27]. The severe late complication rate from this combined treatment is not different from the rate quoted with the same glossary in patients treated with TABLE III Four-year
clinical complication?.
Type of complication
Proctitis Diarrhoea Small bowel injury Cystitis Bladder incontinence Renal Pelvis fibrosis
No. of patients
3 2 1 1 1 5 4
corresponds
TABLE IV
rate (%)b
(SD.)
Four-year biological complications. ing to grade and type”.
20.5 6.5 4.8 11.1 8.3 21.4 18.8
(9.9) (4.5) (4.7) (10.5)
a Complications were graded according to a glossary published in 1980 [3]. b Estimated using Kaplan-Meier method.
to the number of
the same radiotherapy doses without chemotherapy [8]. NO lethal complication was observed. This type of association did not increase the 4-year complication rate. It is not possible from this non-randomized trial to determine whether the combination of chemotherapy and radiotherapy is superior to the use of radiotherapy alone. The 4-year survival rate is not different from the rate observed with radiation therapy only [8]. The 4-year loco-regional failure rate remains high. However, all the patients had either advanced stage III or stage IV disease. In this association, if chemotherapy and radiotherapy had an additive mechanism, small tumours would be expected to have a better response-rate than larger tumours [2,22]. Moreover, in this type of association, radiotherapy is lenghtened with a gap of 2 weeks in the middle of the treatment. Since the time we initiated this trial, some authors have suggested that, when overall treatment time is lengthenod,
4-Year complication
(8) (8.6) (8.7)
2 (1) 2
Grade
Type
Haemoglobin White blood counts Creatininaemia a Complications tion [28].
Number of patients accord-
1
2
3
2 3 2
2 2 2
2
were graded according to the
WHOclassifica-
126 radioresistance might be increased [7,25]. Repopulation could play an important role in this increased radioresistance. In conclusion, chemotherapy interdigitated with radiotherapy in the treatment of advanced cervical carcinoma is feasible without toxicity enhancement. It is impossible to determine the efficacy of such a combined treatment because of the small number of patients. However, we have stopped this type of treatment, mainly because of the poor cost-benefit ratio of such an alternating schedule. The concomitant use of chemotherapy and radiation therapy couid be an alternative. Chemotherapeutic agents like cDDP or hydroxyurea given during radiotherapy have been reported to improve the survival [4,21]. Prospective studies comparing radiotherapy with radiotherapy and chemotherapy are needed in advanced cervical carcinoma. Another alternative is the use of “new” radiosensitizers. RO-8799 is presently under evaluation in a prospective randomized trial in uterine cervix carcinoma, in which two of us are involved.
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27 Van den Burg, M.E.L., Subandono. A.J., Mangioni. C.. De Oliveira. CF., Zola, P., Pecorelli, S., Van Oosterom, A.T. and Vermorken, J.B. Vincristine. Bleomycin, MitomycinC, Cisplatin as additive treatment to radiotherapy in poor risk patients with squamous cell carcinoma of the uterine cervix. Proceedings ESMO IO (Abstra) 264, 1984. 28 WHO. Handbook for reporting results of cancer treatment. World Health Organization, Geneva, 1979. 29 Woodman, R.J., Sirica, A.E. and Gang, N. The enhanced therapeutic effect of cisplatinum (II) Diamminodirhloride against K 1210 leukemia when combined with Cyclophosphamide or 1, 2-bis (3.5 Dioxopiperazine-I-yl) propane or several other antitumor agents. Chemotherapy 18: 169-l 83, 1973.